Details of the Drug

General Information of Drug (ID: DMEQL9U)

• Drug Name: Benzydamine
• Synonyms: Bencidamina; Benzidamina; Benzidamine; Benzindamine; Benzydaminum; Benzidamina [DCIT]; Benzydamine Monohydrochoride; C 1523; Apo-Benzydamine; Bencidamina [INN-Spanish]; Benzydamine (INN); Benzydamine [INN:BAN]; Benzydaminum [INN-Latin]; Apo-Benzydamine (TN); {3-[(1-benzyl-1H-indazol-3-yl)oxy]propyl}dimethylamine; 1-Benzyl-3-(3-(dimethylamino)propoxy)-1H-indazole; 3-(1-benzylindazol-3-yl)oxy-N,N-dimethylpropan-1-amine; 3-[(1-benzyl-1H-indazol-3-yl)oxy]-N,N-dimethylpropan-1-amine

Indication

Disease Entry	ICD 11	Status	REF
Chemotherapy or radiotherapy-induced mucositis	DA42-DA60	Discontinued in Phase 2	[1]

• Therapeutic Class: Analgesics
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 309.4
  Topological Polar Surface Area (xlogp); 3.9
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 0
  Hydrogen Bond Acceptor Count (hbondacc); 3
• ADMET Property:
  Bioavailability: 87% of drug becomes completely available to its intended biological destination(s) [2]
  Clearance: The sytemic clearance of drug is 170 mL/min [3]
  Elimination: The relatively high lipid solubility of the weak base benzydamine is thought to be associated with considerable passive resorption within the renal tubule, which suggests that only approximately 5% of benzydamine is excreted unchanged in the urine [4]
  Half-life: The concentration or amount of drug in body reduced by one-half in 13 hours [5]
  Metabolism: The drug is metabolized via oxidation, dealkylation, and conjugation into hydroxy, dealkylated, and N-oxide metabolites [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.8% [6]
  Vd: The volume of distribution (Vd) of drug is 10 L [4]
• Chemical Identifiers:
  Formula: C19H23N3O
  IUPAC Name: 3-(1-benzylindazol-3-yl)oxy-N,N-dimethylpropan-1-amine
  Canonical SMILES: CN(C)CCCOC1=NN(C2=CC=CC=C21)CC3=CC=CC=C3
  InChI: InChI=1S/C19H23N3O/c1-21(2)13-8-14-23-19-17-11-6-7-12-18(17)22(20-19)15-16-9-4-3-5-10-16/h3-7,9-12H,8,13-15H2,1-2H3
  InChIKey: CNBGNNVCVSKAQZ-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 12555
  ChEBI ID: CHEBI:94563
  CAS Number: 642-72-8
  DrugBank ID: DB09084
  TTD ID: D06FJO
  INTEDE ID: DR0199

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Prostaglandin G/H synthase (COX)	TTK0943	PGH1_HUMAN; PGH2_HUMAN	Inhibitor	[1]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[7]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Substrate	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Substrate	[7]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Substrate	[7]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[9]
Dimethylaniline oxidase 4 (FMO4)	DEGAZ8O	FMO4_HUMAN	Substrate	[7]

References

• [1] Emerging drugs for chemotherapy-induced mucositis. Expert Opin Emerg Drugs. 2008 Sep;13(3):511-22.
• [2] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [3] Quane PA, Graham GG, Ziegler JB: Pharmacology of benzydamine. Inflammopharmacology. 1998;6(2):95-107. doi: 10.1007/s10787-998-0026-0.
• [4] Baldock GA, Brodie RR, Chasseaud LF, Taylor T, Walmsley LM, Catanese B: Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects. Biopharm Drug Dispos. 1991 Oct;12(7):481-92.
• [5] Electronic Medicines Compedium Benzydamine Hydrochloride 0.15% w/v Mouthwash Monograph
• [6] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [7] In vitro evaluation of potential in vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms. Br J Clin Pharmacol. 2000 Oct;50(4):311-4.
• [8] Characterization of moclobemide N-oxidation in human liver microsomes. Xenobiotica. 2001 Jul;31(7):387-97.
• [9] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [10] Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer. 2007 Mar 1;109(5):957-65.
• [11] Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica. 1998 Jun;28(6):539-47.
• [12] Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75.
• [13] Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013 Feb;41(2):263-9.
• [14] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [15] Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012 Apr;165(8):2787-98.
• [16] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [17] The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. Biochem Pharmacol. 1994 Jul 19;48(2):267-76.
• [18] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [19] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [20] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [21] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [22] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [23] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [24] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [25] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [26] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [27] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
• [28] Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitutions on steroid hydroxylase specificity. Pharmacogenetics. 2000 Aug;10(6):519-30.
• [29] Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002 Aug;30(8):869-74.
• [30] Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism. 2007 Jul;56(7):887-94.
• [31] Preferred orientations in the binding of 4'-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and 15N-NMR relaxation studies. J Med Chem. 1994 Mar 18;37(6):860-7.
• [32] Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P450 2Cs. Biochemistry. 1999 Oct 26;38(43):14264-70.
• [33] A common CYP1B1 polymorphism is associated with 2-OHE1/16-OHE1 urinary estrone ratio. Clin Chem Lab Med. 2005;43(7):702-6.
• [34] Cytochromes P450 in crustacea. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1998 Nov;121(1-3):157-72.
• [35] Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone. Biochem J. 1998 Apr 1;331 ( Pt 1):273-81.
• [36] Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab. 2007 Aug;8(6):554-62.
• [37] Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5.
• [38] Effect of genetic polymorphism on the metabolism of endogenous neuroactive substances, progesterone and p-tyramine, catalyzed by CYP2D6. Brain Res Mol Brain Res. 2004 Oct 22;129(1-2):117-23.
• [39] CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010 Jan;12(1):7-15.
• [40] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [41] Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
• [42] Pharmacogenetics of schizophrenia. Am J Med Genet. 2000 Spring;97(1):98-106.
• [43] Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol. 1999 Mar;73(2):65-70.
• [44] Structure-activity relationship for human cytochrome P450 substrates and inhibitors. Drug Metab Rev. 2002 Feb-May;34(1-2):69-82.
• [45] Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol. 2005 Jul;289(1):G54-63.
• [46] Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 2003 May;63(5):1687-96.
• [47] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [48] Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res. 2010 Mar;44(3):340-55.
• [49] A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300.
• [50] Novel metabolic pathway of estrone and 17beta-estradiol catalyzed by cytochrome P-450. Drug Metab Dispos. 2000 Feb;28(2):110-2.
• [51] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [52] CYP2E1 and clinical features in alcoholics. Neuropsychobiology. 2003;47(2):86-9.
• [53] High-dose rabeprazole/amoxicillin therapy as the second-line regimen after failure to eradicate H. pylori by triple therapy with the usual doses of a proton pump inhibitor, clarithromycin and amoxicillin. Hepatogastroenterology. 2003 Nov-Dec;50(54):2274-8.
• [54] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [55] Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006 Mar 13;25(11):1679-91.
• [56] CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat. 2009 May;115(2):391-6.
• [57] Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1995 Dec;353(1):116-21.
• [58] A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother. 1998 May;32(5):554-63.
• [59] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [60] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [61] Mechanism of action of paracetamol. Am J Ther. 2005 Jan-Feb;12(1):46-55.
• [62] Diclofenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease agonist-induced contractions of the pig isolated ureter. Urol Res. 2000 Dec;28(6):376-82.
• [63] Cyclooxygenase inhibitors: instrumental drugs to understand cardiovascular homeostasis and arterial thrombosis. Cardiovasc Hematol Disord Drug Targets. 2008 Dec;8(4):268-77.
• [64] Comparison of the efficacy and tolerability of dexibuprofen and celecoxib in the treatment of osteoarthritis of the hip. Int J Clin Pharmacol Ther. 2003 Apr;41(4):153-64.
• [65] Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H425-32.
• [66] Interactions of PGH synthase isozymes-1 and -2 with NSAIDs. Ann N Y Acad Sci. 1994 Nov 15;744:50-7.
• [67] The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer Res. 2007 Apr 1;67(7):3254-62.
• [68] Aceclofenac spares cyclooxygenase 1 as a result of limited but sustained biotransformation to diclofenac. Clin Pharmacol Ther. 2003 Sep;74(3):222-35.
• [69] The analgesic NSAID lornoxicam inhibits cyclooxygenase (COX)-1/-2, inducible nitric oxide synthase (iNOS), and the formation of interleukin (IL)-6 in vitro. Inflamm Res. 1999 Jul;48(7):369-79.
• [70] Modulation of arachidonic acid metabolism by orally administered morniflumate in man. Agents Actions. 1991 Jul;33(3-4):233-9.